scholarly journals Type S Non Ribosomal Peptide Synthetases for the rapid generation of tailor-made peptide libraries

2021 ◽  
Author(s):  
Nadya Abbood ◽  
Tien Duy Vo ◽  
Jonas Watzel ◽  
Kenan A. J. Bozhueyuek ◽  
Helge B. Bode
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
De Novo ◽  
Chemical Space ◽  
Biologically Relevant ◽  
Peptide Synthetases ◽  
Medical Needs ◽  
Natural Product Research ◽  
Rapid Generation ◽  
Traditional Natural

Bacterial natural products in general, and non-ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatised as inefficient, time-, labour-, and cost-intensive. Combinatorial chemistry, on the other hand, can produce new molecules in greater numbers, cheaper and in less time than traditional natural product discovery, but also fails to meet current medical needs due to the limited biologically relevant chemical space that can be addressed. Consequently, methods for the high throughput generation of new-to-nature natural products would offer a new approach to identifying novel bioactive chemical entities for the hit to lead phase of drug discovery programms. As a follow-up to our previously published proof-of-principle study on generating bipartite type S non-ribosomal peptide synthetases (NRPSs), we now envisaged the de novo generation of non-ribosomal peptides (NRPs) on an unreached scale. Using synthetic zippers, we split NRPS in up to three subunits and rapidly generated different bi- and tripartite NRPS libraries to produce 49 peptides, peptide derivatives, and de novo peptides at good titres up to 145 mgL-1. A further advantage of type S NRPSs not only is the possibility to easily expand the created libraries by re-using previously created type S NRPS, but that functions of individual domains as well as domain-domain interactions can be studied and assigned rapidly.

scholarly journals Natural product fragment combination to performance-diverse pseudo-natural products

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Grigalunas ◽  
Annina Burhop ◽  
Sarah Zinken ◽  
Axel Pahl ◽  
José-Manuel Gally ◽  
...  
Keyword(s):  
Natural Products ◽  
Product Design ◽  
Natural Product ◽  
Chemical Space ◽  
Biological Evaluation ◽  
Product Structure ◽  
Biologically Relevant ◽  
Biologically Relevant Chemical Space

AbstractNatural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

scholarly journals Towards the de Novo Design of HIV-1 Protease Inhibitors Based on Natural Products

2021 ◽  
Author(s):  
Ana L. Chávez-Hernández ◽  
K. Eurídice Juárez-Mercado ◽  
Fernanda I. Saldívar-González ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Protease Inhibitors ◽  
De Novo ◽  
Chemical Space ◽  
Public Health Problem ◽  
Building Blocks ◽  
De Novo Design ◽  
Viral Protease ◽  
Hiv 1

The acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are only a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, new novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual-focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available at https://figshare.com/s/ceb58d58e8f5585ce67e.

scholarly journals Natural product-informed exploration of chemical space to enable bioactive molecular discovery

2021 ◽  
Author(s):  
Adam Nelson ◽  
George Karageorgis
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Chemical Space ◽  
Bioactive Molecules ◽  
Biological Processes ◽  
Biologically Relevant ◽  
Systematic Exploration ◽  
Biologically Relevant Chemical Space

Natural products serve as starting points for the systematic exploration of biologically-relevant chemical space to afford bioactive molecules which can be used to study biological processes.

scholarly journals Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1805
Author(s):  
Ana L. Chávez-Hernández ◽  
K. Eurídice Juárez-Mercado ◽  
Fernanda I. Saldívar-González ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Protease Inhibitors ◽  
De Novo ◽  
Chemical Space ◽  
Public Health Problem ◽  
Building Blocks ◽  
De Novo Design ◽  
Viral Protease ◽  
Hiv 1

Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available in the supplementary material.

scholarly journals Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 107
Author(s):  
Rafael de Felício ◽  
Patricia Ballone ◽  
Cristina Freitas Bazzano ◽  
Luiz F. G. Alves ◽  
Renata Sigrist ◽  
...  
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Natural Product ◽  
Deep Sea ◽  
Chemical Space ◽  
Bacterial Genome ◽  
Vast Number ◽  
Bacterial Metabolites ◽  
Laboratory Conditions ◽  
Deep Sea Bacteria

Bacterial genome sequencing has revealed a vast number of novel biosynthetic gene clusters (BGC) with potential to produce bioactive natural products. However, the biosynthesis of secondary metabolites by bacteria is often silenced under laboratory conditions, limiting the controlled expression of natural products. Here we describe an integrated methodology for the construction and screening of an elicited and pre-fractionated library of marine bacteria. In this pilot study, chemical elicitors were evaluated to mimic the natural environment and to induce the expression of cryptic BGCs in deep-sea bacteria. By integrating high-resolution untargeted metabolomics with cheminformatics analyses, it was possible to visualize, mine, identify and map the chemical and biological space of the elicited bacterial metabolites. The results show that elicited bacterial metabolites correspond to ~45% of the compounds produced under laboratory conditions. In addition, the elicited chemical space is novel (~70% of the elicited compounds) or concentrated in the chemical space of drugs. Fractionation of the crude extracts further evidenced minor compounds (~90% of the collection) and the detection of biological activity. This pilot work pinpoints strategies for constructing and evaluating chemically diverse bacterial natural product libraries towards the identification of novel bacterial metabolites in natural product-based drug discovery pipelines.

scholarly journals MeFSAT: a curated natural product database specific to secondary metabolites of medicinal fungi

RSC Advances ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 2596-2607
Author(s):  
R. P. Vivek-Ananth ◽  
Ajaya Kumar Sahoo ◽  
Kavyaa Kumaravel ◽  
Karthikeyan Mohanraj ◽  
Areejit Samal
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Natural Product ◽  
Chemical Space ◽  
Therapeutic Uses ◽  
Medicinal Fungi ◽  
Fungal Natural Products

First dedicated manually curated resource on secondary metabolites and therapeutic uses of medicinal fungi. Cheminformatics based analysis of the chemical space of fungal natural products.

scholarly journals Bridging the gap between natural product synthesis and drug discovery

2020 ◽  
Vol 37 (11) ◽  
pp. 1436-1453 ◽  
Author(s):  
Nathanyal J. Truax ◽  
Daniel Romo
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
Chemical Space ◽  
Natural Product Synthesis ◽  
Chemical Information

Various synthetic strategies have been developed to explore natural products as an enduring source of chemical information useful for probing biological relevant chemical space and impacting drug discovery.

scholarly journals A practical guide for transparent reporting of research on natural products in the British Journal of Pharmacology : Reproducibility of natural product research

2020 ◽  
Vol 177 (10) ◽  
pp. 2169-2178 ◽  
Author(s):  
Angelo A. Izzo ◽  
Mauro Teixeira ◽  
Steve P.H. Alexander ◽  
Giuseppe Cirino ◽  
James R. Docherty ◽  
...  
Keyword(s):  
Natural Products ◽  
British Journal ◽  
Natural Product ◽  
Practical Guide ◽  
Transparent Reporting ◽  
Natural Product Research

Expansion of chemical space for natural products by uncommon P450 reactions

2017 ◽  
Vol 34 (9) ◽  
pp. 1061-1089 ◽  
Author(s):  
Xingwang Zhang ◽  
Shengying Li
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Protein Interactions ◽  
Chemical Space ◽  
Protein Protein Interactions ◽  
Natural Product Biosynthesis ◽  
Space Expansion

This review focuses on unusual P450 reactions related to new chemistry, skeleton construction, structure re-shaping, and protein–protein interactions in natural product biosynthesis, which play significant roles in chemical space expansion for natural products.

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